ClinVar Miner

Submissions for variant NM_001114753.3(ENG):c.321_322delinsTT (p.His108Tyr) (rs1060501425)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000473361 SCV000546134 uncertain significance Hereditary hemorrhagic telangiectasia 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 108 of the ENG protein (p.His108Tyr). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with hereditary hemorrhagic telangiectasia, and a different pathogenic ENG variant was also detected in this individual (PMID: 25312062). It is unknown if these variants are on the same or opposite chromosomes, therefore the clinical significance of the c.321_322delGCinsTT variant is unclear. Experimental studies have shown that this missense change does not affect ENG cellular localization and response to BMP9 (PMID: 25312062). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000600129 SCV000713059 uncertain significance not specified 2017-04-03 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.His108Tyr (c. 321_322delinsTT) variant in ENG results from a deletion and insertion of 2 conse cutive bases in cis and creates a missense change. This variant has been reporte d in 1 French individual with Hereditary Hemorrhagic Telangiectasia (HHT); howev er, this individual carried a second variant in ENG that was sufficient to expla in their disease (Mallet 2015). The p.His108Tyr variant has also been identified in 15/66242 European chromosomes by the Exome Aggregation Consortium (ExAC, htt p://exac.broadinstitute.org; dbSNP rs756897517). In vitro functional studies pro vide some evidence that this change may not impact protein function (Mallet 2015 ). However, these types of assays may not accurately represent biological functi on. In summary, while the clinical significance of the p.His108Tyr variant is un certain, these data suggest that it is more likely to be benign.

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